DESCRIPTION: The applicant proposes to test the novel hypothesis that the protein product of the c-cbl protooncogene (Cbl) is a regulator of EGFR/ErbB2 signal transduction in mammary epithelial cells. To test this, the applicant will express the putative EGF-regulatory domain of Cbl (Cbl-N) or its inactive mutant (Cbl-N/G306E) in human MECs and quantify their mitogenic response to EGF, receptor internalization and sub-cellular localization of EGFR/ErbB2. Screening of degenerate phosphopetide libraries, and phosphopeptide competition to identify Cbl-binding site(s) on the EGFR/ErbB2 and mutate these sites to ascertain the nature of Cbl's regulatory influence. The applicant proposes that the accomplishment of this proposal represents a critical step forward to identify new targets for the rational therapeutic strategies against breast cancer.